CA2951911A1 - Tank-binding kinase inhibitor compounds - Google Patents
Tank-binding kinase inhibitor compounds Download PDFInfo
- Publication number
- CA2951911A1 CA2951911A1 CA2951911A CA2951911A CA2951911A1 CA 2951911 A1 CA2951911 A1 CA 2951911A1 CA 2951911 A CA2951911 A CA 2951911A CA 2951911 A CA2951911 A CA 2951911A CA 2951911 A1 CA2951911 A1 CA 2951911A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- cycloalkyl
- compound
- membered heterocyclyl
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 258
- 229940043355 kinase inhibitor Drugs 0.000 title description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 228
- 125000000623 heterocyclic group Chemical group 0.000 claims description 227
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 137
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 127
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 123
- -1 C1-6 alkyl-OH Chemical group 0.000 claims description 117
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 111
- 229910052736 halogen Inorganic materials 0.000 claims description 110
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 110
- 150000003839 salts Chemical class 0.000 claims description 97
- 125000005843 halogen group Chemical group 0.000 claims description 92
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 80
- 125000004043 oxo group Chemical group O=* 0.000 claims description 76
- 150000002367 halogens Chemical class 0.000 claims description 75
- 125000003118 aryl group Chemical group 0.000 claims description 73
- 125000004429 atom Chemical group 0.000 claims description 56
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 55
- 125000003003 spiro group Chemical group 0.000 claims description 54
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 51
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 46
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 40
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 40
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 34
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000001188 haloalkyl group Chemical group 0.000 claims description 23
- 125000001153 fluoro group Chemical group F* 0.000 claims description 19
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- VMWJCFLUSKZZDX-UHFFFAOYSA-N n,n-dimethylmethanamine Chemical compound [CH2]N(C)C VMWJCFLUSKZZDX-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 102000001284 I-kappa-B kinase Human genes 0.000 claims description 2
- 108060006678 I-kappa-B kinase Proteins 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims 6
- 102100038192 Serine/threonine-protein kinase TBK1 Human genes 0.000 claims 2
- 101710106944 Serine/threonine-protein kinase TBK1 Proteins 0.000 claims 2
- 150000001350 alkyl halides Chemical class 0.000 claims 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 40
- 238000000034 method Methods 0.000 abstract description 28
- 239000000203 mixture Substances 0.000 description 290
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 278
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 250
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 249
- 239000000243 solution Substances 0.000 description 200
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 165
- 239000011541 reaction mixture Substances 0.000 description 152
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 151
- 229910003827 NRaRb Inorganic materials 0.000 description 140
- 239000007821 HATU Substances 0.000 description 124
- 239000000047 product Substances 0.000 description 117
- 239000012044 organic layer Substances 0.000 description 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 95
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 93
- 238000005160 1H NMR spectroscopy Methods 0.000 description 91
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 90
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 86
- 238000002953 preparative HPLC Methods 0.000 description 86
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- 229910052938 sodium sulfate Inorganic materials 0.000 description 84
- 235000011152 sodium sulphate Nutrition 0.000 description 84
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 80
- 230000002829 reductive effect Effects 0.000 description 69
- 239000007832 Na2SO4 Substances 0.000 description 66
- 206010012812 Diffuse cutaneous mastocytosis Diseases 0.000 description 57
- 238000000746 purification Methods 0.000 description 51
- 239000007787 solid Substances 0.000 description 46
- 238000006243 chemical reaction Methods 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 41
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 40
- 229960004275 glycolic acid Drugs 0.000 description 40
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 39
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 36
- BSEXNZMHLUMQKR-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1.NC(=O)C1CC1 BSEXNZMHLUMQKR-UHFFFAOYSA-N 0.000 description 36
- 238000010898 silica gel chromatography Methods 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 30
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 29
- 239000002585 base Substances 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
- 239000002253 acid Substances 0.000 description 26
- 239000002904 solvent Substances 0.000 description 25
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 24
- 239000012267 brine Substances 0.000 description 24
- 238000005859 coupling reaction Methods 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 23
- 239000000872 buffer Substances 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 22
- 229910052757 nitrogen Inorganic materials 0.000 description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- 230000008878 coupling Effects 0.000 description 20
- 238000010168 coupling process Methods 0.000 description 20
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 19
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 19
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 238000001816 cooling Methods 0.000 description 16
- 125000004404 heteroalkyl group Chemical group 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- 229910000029 sodium carbonate Inorganic materials 0.000 description 14
- 235000017550 sodium carbonate Nutrition 0.000 description 14
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 229910052751 metal Inorganic materials 0.000 description 12
- 239000002184 metal Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000004007 reversed phase HPLC Methods 0.000 description 12
- 229910052701 rubidium Inorganic materials 0.000 description 12
- 238000000926 separation method Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 11
- 125000003342 alkenyl group Chemical group 0.000 description 11
- 229910021529 ammonia Inorganic materials 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- GISYXRBCSOIMTM-ZETCQYMHSA-N tert-butyl (4s)-3,3-difluoro-4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](O)C(F)(F)C1 GISYXRBCSOIMTM-ZETCQYMHSA-N 0.000 description 11
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 10
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 9
- DUKKRSPKJMHASP-UHFFFAOYSA-N 6-chloropyrimidin-4-amine Chemical compound NC1=CC(Cl)=NC=N1 DUKKRSPKJMHASP-UHFFFAOYSA-N 0.000 description 9
- KKWGIEHCPKHJLB-UHFFFAOYSA-N N-[6-(3-cyano-4-fluorophenyl)pyrimidin-4-yl]cyclopropanecarboxamide Chemical compound C(#N)C=1C=C(C=CC=1F)C1=CC(=NC=N1)NC(=O)C1CC1 KKWGIEHCPKHJLB-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 102100021857 Inhibitor of nuclear factor kappa-B kinase subunit epsilon Human genes 0.000 description 8
- RGFNDLPTRUWLRN-UHFFFAOYSA-N N-[4-(3-cyano-4-fluorophenyl)pyridin-2-yl]cyclopropanecarboxamide Chemical compound C(#N)C=1C=C(C=CC=1F)C1=CC(=NC=C1)NC(=O)C1CC1 RGFNDLPTRUWLRN-UHFFFAOYSA-N 0.000 description 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- RBNPOMFGQQGHHO-UHFFFAOYSA-N -2,3-Dihydroxypropanoic acid Natural products OCC(O)C(O)=O RBNPOMFGQQGHHO-UHFFFAOYSA-N 0.000 description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 7
- 101001043761 Homo sapiens Inhibitor of nuclear factor kappa-B kinase subunit epsilon Proteins 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- RBNPOMFGQQGHHO-REOHCLBHSA-N L-glyceric acid Chemical compound OC[C@H](O)C(O)=O RBNPOMFGQQGHHO-REOHCLBHSA-N 0.000 description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 7
- 239000007822 coupling agent Substances 0.000 description 7
- 238000006880 cross-coupling reaction Methods 0.000 description 7
- 239000002480 mineral oil Substances 0.000 description 7
- 235000010446 mineral oil Nutrition 0.000 description 7
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 7
- XRNLYXKYODGLMI-SFYZADRCSA-N tert-butyl (3r,4s)-3-fluoro-4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](F)C1 XRNLYXKYODGLMI-SFYZADRCSA-N 0.000 description 7
- BAQKUNMKVAPWGU-UHFFFAOYSA-N 4-bromopyridin-2-amine Chemical compound NC1=CC(Br)=CC=N1 BAQKUNMKVAPWGU-UHFFFAOYSA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 6
- 150000001805 chlorine compounds Chemical class 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 238000000638 solvent extraction Methods 0.000 description 6
- IVOZWVIZHBGIIT-UHFFFAOYSA-N 2-cyano-4-[6-(cyclopropanecarbonylamino)pyrimidin-4-yl]benzoic acid Chemical compound C(#N)C1=C(C(=O)O)C=CC(=C1)C1=NC=NC(=C1)NC(=O)C1CC1 IVOZWVIZHBGIIT-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 101150073096 NRAS gene Proteins 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 150000003927 aminopyridines Chemical class 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 150000001642 boronic acid derivatives Chemical class 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000012047 saturated solution Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
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Classifications
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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US62/425,396 | 2016-11-22 |
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BR (1) | BR112017002594A2 (zh) |
CA (2) | CA3006772A1 (zh) |
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CR (1) | CR20180320A (zh) |
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CN111377850B (zh) * | 2018-12-31 | 2022-10-18 | 艾琪康医药科技(上海)有限公司 | 一种手性n-取代-3,3-二氟-4-羟基哌啶衍生物及其制备方法 |
WO2020232330A1 (en) * | 2019-05-15 | 2020-11-19 | Biogen Ma Inc. | Inhibiting agents for bruton's tyrosine kinase |
WO2020251965A1 (en) * | 2019-06-10 | 2020-12-17 | Board Of Regents, The University Of Texas System | Combinatorial therapy targeting parp1 and rtk |
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2016
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- 2016-12-15 MA MA044112A patent/MA44112A/fr unknown
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- 2016-12-15 WO PCT/US2016/067022 patent/WO2017106556A1/en active Application Filing
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CN108430993A (zh) | 2018-08-21 |
BR112017002594A2 (pt) | 2017-12-19 |
CU20180059A7 (es) | 2018-10-04 |
SG11201804294WA (en) | 2018-07-30 |
CO2018006051A2 (es) | 2018-07-10 |
KR20180094976A (ko) | 2018-08-24 |
AU2016370916A1 (en) | 2018-06-07 |
US10316049B2 (en) | 2019-06-11 |
ECSP18044917A (es) | 2018-06-30 |
CL2018001586A1 (es) | 2018-10-05 |
EA201891024A1 (ru) | 2018-12-28 |
US20170174713A1 (en) | 2017-06-22 |
WO2017106556A1 (en) | 2017-06-22 |
IL259719A (en) | 2018-07-31 |
TW201737913A (zh) | 2017-11-01 |
UY37036A (es) | 2017-06-30 |
DOP2018000147A (es) | 2018-10-31 |
PH12018501151A1 (en) | 2019-01-28 |
PE20181073A1 (es) | 2018-07-04 |
MA44112A (fr) | 2018-10-31 |
TWI639427B (zh) | 2018-11-01 |
MX2018007421A (es) | 2018-08-15 |
JP2019500368A (ja) | 2019-01-10 |
CR20180320A (es) | 2018-08-21 |
CA3006772A1 (en) | 2017-06-22 |
EP3394044A1 (en) | 2018-10-31 |
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